1. Field of the Invention
The present invention relates to methods and materials for the synthesis of organic compounds.
2. Description of Related Art
Methodologies involving the synthesis of organic molecules play an important role in many technical fields. Materials science, agriculture, biology, and medicine, rely on organic compounds produced by synthetic methods for their ongoing successes and future progress. Consequently, in the past century artisans have devoted significant efforts to the development of new methodologies for the synthesis of various organic compounds. The large number of synthetic methodologies known in the art as a result of these endeavors allows artisans to construct molecules of great complexity. As complex organic molecules become more and more important in a number of scientific disciplines, the ability to prepare key synthetic entities in both a practical and economical fashion becomes increasingly more valuable (see, e.g. Wender et al., Acc. Chem. Res. 2008, 41, 40-49).
Of the many synthetic methods used to generate organic compounds, transition metal-catalyzed cross-coupling reactions are known as one of the most effective means of constructing carbon-carbon (C—C) and carbon-heteroatom (C—X) bonds (see, e.g. Negishi et al., Acc. Chem. Res. 1982, 15, 340-348; Metal-Catalyzed Cross-Coupling Reactions; Diedrich, F., Meijere, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2.; Hassan et al., Chem. Rev. 2002, 102, 1359-1469; Topics in Current Chemistry; Miyaura, N., Ed.; Vol. 219; Springer-Verlag: New York, 2002; Corbet et al.,Rev. 2006, 106, 2651-2710; Negishi, Bull. Chem. Soc. Jpn. 2007, 80, 233-257). These bonds are commonly found in a variety of compounds, and, for example, are ubiquitous in drug substances. Illustrating this, eight of the top twenty best selling drug compounds in 2007 possessed either an aryl-aryl C—C bond or an aryl C—X bond. The combined 2007 sales for these compounds amounted to nearly twenty billion dollars (compounds including for example, Lipitor®, Singular®, Seroquel®, and Celebrex®).
While methodologies for the cross-coupling of aryl halides have improved significantly over the past decade, less progress has been made in methods for the coupling of the corresponding phenol derivatives. Because phenols are typically cheap and readily available, and further because oxygenation can be used to direct the installation of functional groups on an aromatic ring, practical methods that allow for the cross-coupling of phenol derivatives are extremely desirable. Although some methods for cross-coupling phenol derivatives exist, there is a need to improve existing methodology (see, e.g. the schematic shown in FIG. 1A). Of the known methods for phenol coupling, the most common involve formation and reaction of the corresponding aryl triflates (see, e.g. Negishi et al., Acc. Chem. Res. 1982, 15, 340-348; Metal-Catalyzed Cross-Coupling Reactions; Diedrich, F., Meijere, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2.; Hassan et al., Chem. Rev. 2002, 102, 1359-1469; Topics in Current Chemistry; Miyaura, N., Ed.; Vol. 219; Springer-Verlag: New York, 2002;Corbet et al., Rev. 2006, 106, 2651-2710; Negishi, Bull. Chem. Soc. Jpn. 2007, 80, 233-257). Unfortunately, aryl triflates species used in phenol coupling reactions are relatively costly. In addition, these compounds are susceptible to base-promoted hydrolysis (see, e.g. Molander et al., J. Org. Chem. 2002, 67, 8416-8423). Moreover, while aryl tosylates (-OTs) and mesylates (-OMs) have also been used as cross-coupling partners, these molecules do not appear to have general utilities (see, e.g. Tang et al., J. Am. Chem. Soc. 2004, 126, 3058-3059; Percec et al., J. Org. Chem. 2004, 69, 3447-3452; Zhang et al., J. Org. Chem. 2007, 72, 9346-9349; Munday et al., J. Am. Chem. Soc. 2008, 130, 2754-2755). Cross-coupling reactions of aryl methyl ethers (OMe), although largely limited to Kumada couplings using harsh Grignard reagents, are also known in the art (see, e.g. Wenkert et al., J. Am. Chem. Soc. 1979, 101, 2246-2247; Wenkert et al., J. Org. Chem. 1984, 49, 4894-4899; Dankwardt et al., Angew. Chem. Int. Ed. 2004, 43, 2428-2432; and Guan et al., Chem. Commun. 2008, 1437-1439). A recent report by Chatani and co-workers somewhat expands the scope of this cross-coupling to arylboronic acids, provided that the aryl ether cross-coupling partner is electron-deficient and preferably contained within a highly reactive fused aromatic ring system (see, e.g. Tobisu et al., Angew. Chem. Int. Ed. 2008, 47, 4866-4869). Despite some advances in this technology, general methodologies that provide efficient and cost-effective cross-coupling of phenol derivatives have yet to be realized.